SN-positive Melanoma Research Articles

Impact of the changes in the completion lymph node dissection criteria and approval of adjuvant therapies on the real-world outcomes of Japanese stage III melanoma patients.

Completion lymph node dissection (CLND) has long been the standard treatment for stage III melanomas identified as metastasis on the sentinel node (SN-positive). Two major changes occurred in 2017 and 2018, the change in the CLND criteria for SN-positive patients and the approval of several adjuvant therapies could revolutionize such management approach. However, their effects have not been fully investigated on the real-world outcomes of stage III melanoma patients. Therefore, we investigated the impact of these changes on the prognosis of Japanese stage III melanoma patients. Totally, 119 stage III, SN-positive melanoma patients were included. They were categorized into those diagnosed as SN-positive between January 2015 and June 2017 (pre-June 2017 group) and between July 2017 and December 2019 (post-July 2017 group). Recurrence-free survival (RFS), overall survival, and prognostic factors were analyzed. The frequency of patients who received CLND was significantly higher in the pre-June 2017 group (p = 0.001), and those who received adjuvant therapy were significantly higher in the post-July 2017 group (p < 0.001). The 2-year RFS was 50.1% and 68.5% in the pre-June and post-July 2017 groups, respectively (p = 0.049). Cox proportional hazards model analysis for RFS showed that adjuvant therapies reduce the risk of recurrence (hazard ratio 0.37; 95% confidence interval 0.14-0.99; p = 0.047). Changes in the CLND criteria in SN-positive patients and the approval of adjuvant therapies for stage III melanomas have significantly impacted Japanese melanoma medicine. Adjuvant therapy tended to prolong patient's RFS while omitting immediate CLND had no significant negative influence on it.

The EORTC-DeCOG nomogram adequately predicts outcomes of patients with sentinel node–positive melanoma without the need for completion lymph node dissection

PurposeBased on recent advances in the management of patients with sentinel node (SN)–positive melanoma, we aimed to develop prediction models for recurrence, distant metastasis (DM) and overall mortality (OM). MethodsThe derivation cohort consisted of 1080 patients with SN-positive melanoma from nine European Organization for Research and Treatment of Cancer (EORTC) centres. Prognostic factors for recurrence, DM and OM were studied with Cox regression analysis. Significant factors were incorporated in the models. Performance was assessed by discrimination (c-index) and calibration in cross-validation across centres. The models were externally validated using a prospective cohort consisting of 705 German patients with SN-positive: 473 trial participants of the German Dermatologic Cooperative Oncology Group study (DeCOG-SLT) and 232 screened patients. A nomogram was developed for graphical presentation. ResultsThe final model for recurrence and the calibrated models for DM and OM included ulceration, age, SN tumour burden and Breslow thickness. The models showed reasonable calibration. The c-index for the recurrence, DM and OM model was 0.68, 0.70 and 0.70, respectively, and 0.70, 0.72 and 0.74, respectively, in external validation. The EORTC-DeCOG model identified a robust low-risk group, with all identified low-risk patients (approximately 4% of the entire population) having a 5-year recurrence probability of <25% and an overall 5-year recurrence rate of 13%. A model including information on completion lymph node dissection (CLND) showed only marginal improvement in model performance. ConclusionsThe EORTC-DeCOG nomogram provides an adequate prognostic tool for patients with SN-positive melanoma, without the need for CLND. It showed consistent results across validation. The nomogram could be used for patient counselling and might aid in adjuvant therapy decision-making.

A prediction tool incorporating the biomarker S-100B for patient selection for completion lymph node dissection in stage III melanoma

IntroductionCompletion lymph node dissection (CLND) in sentinel node (SN)-positive melanoma patients is accompanied with morbidity, while about 80% yield no additional metastases in non-sentinel nodes (NSNs). A prediction tool for NSN involvement could be of assistance in patient selection for CLND. This study investigated which parameters predict NSN-positivity, and whether the biomarker S-100B improves the accuracy of a prediction model. MethodsRecorded clinicopathologic factors were tested for their association with NSN-positivity in 110 SN-positive patients who underwent CLND. A prediction model was developed with multivariable logistic regression, incorporating all predictive factors. Five models were compared for their predictive power by calculating the Area Under the Curve (AUC). A weighted risk score, ‘S-100B Non-Sentinel Node Risk Score’ (SN-SNORS), was derived for the model with the highest AUC. Besides, a nomogram was developed as visual representation. ResultsNSN-positivity was present in 24 (21.8%) patients. Sex, ulceration, number of harvested SNs, number of positive SNs, and S-100B value were independently associated with NSN-positivity. The AUC for the model including all these factors was 0.78 (95%CI 0.69–0.88). SN-SNORS was the sum of scores for the five parameters. Scores of ≤9.5, 10–11.5, and ≥12 were associated with low (0%), intermediate (21.0%) and high (43.2%) risk of NSN involvement. ConclusionsA prediction tool based on five parameters, including the biomarker S-100B, showed accurate risk stratification for NSN-involvement in SN-positive melanoma patients. If validated in future studies, this tool could help to identify patients with low risk for NSN-involvement.

The prognostic significance of sentinel node tumour burden in melanoma patients: An international, multicenter study of 1539 sentinel node-positive melanoma patients

IntroductionSentinel node (SN) biopsy (SNB) and completion lymph node dissection (CLND) when SN-positive have become standard of care in most cancer centres for melanoma. Various SN tumour burden parameters are assessed to determine the heterogeneity of SN-positivity. The aim of the present study was to validate the prognostic significance of various SN tumour burden micromorphometric features and classification schemes in a large cohort of SN-positive melanoma patients. MethodsIn 1539 SN-positive patients treated between 1993 and 2008 at 11 melanoma treatment centres in Europe and Australia, indices of SN tumour burden (intranodal location, tumour penetrative depth (TPD) and maximum size of SN tumour deposits) were evaluated. ResultsNon-subcapsular location, increasing TPD and increasing maximum size were all predictive factors for non-SN (NSN) status and were independently associated with poorer melanoma-specific survival (MSS). Patients with subcapsular micrometastases <0.1mm in maximum dimension had the lowest frequency of NSN metastasis (5.5%). Despite differences in SN biopsy protocols and clinicopathologic features of the patient cohorts (between centres), most SN parameters remained predictive in individual centre populations. Maximum SN tumour size>1mm was the most reliable and consistent parameter independently associated with higher non-SN-positivity, poorer disease-free survival (DFS) and poorer MSS. ConclusionsIn this large retrospective, multicenter cohort study, several parameters of SN tumour burden including intranodal location, TPD and maximum size provided prognostic information, but their prognostic significance varied considerably between the different centres. This could be due to sample size limitations or to differences in SN detection, removal and examination techniques.

Prognosis in patients with sentinel node-positive melanoma without immediate completion lymph node dissection

The therapeutic value of immediate completion lymph node dissection (CLND) for sentinel node (SN)-positive melanoma is unknown. The aim of this study was to evaluate the impact of immediate CLND on the outcome of patients with SN-positive melanoma. Patients with SN metastases treated between 1993 and 2008 at ten cancer centres from the European Organization for Research and Treatment of Cancer Melanoma Group were included in this retrospective study. Maximum tumour size, intranodal location and penetrative depth of SN metastases were measured. Outcome in those who had CLND was compared with that in patients who did not undergo completion lymphadenectomy. Of 1174 patients with SN-positive melanoma, 1113 (94.8 per cent) underwent CLND and 61 (5.2 per cent) did not. Median follow-up for the two groups was 34 and 48 months respectively. In univariable survival analysis, CLND did not significantly influence disease-specific survival (hazard ratio (HR) 0.89, 95 per cent confidence interval 0.58 to 1.37; P = 0.600). However, patients who did not undergo CLND had more favourable prognostic factors. Matched-pair analysis, with matching for age, Breslow thickness, tumour ulceration and SN tumour burden, showed that CLND had no influence on survival (HR 0.86, 0.46 to 1.61; P = 0.640). After adjusting for prognostic factors in multivariable survival analyses, no difference in survival was found. In these two cohorts of patients with SN-positive melanoma and prognostic heterogeneity, outcome was not influenced by CLND.

Publication and Interpretation of Clinical Trial Results: The Need for Caution

When the results of a clinical trial are published, modern information technology ensures that news of the trial outcome is disseminated rapidly to the medical community worldwide, and often to the general public as well, through the media. However, there is always a danger that physicians, patients, and the general public may be inappropriately influenced by the ‘‘spin’’ that is put on what they read or hear, without subjecting the trial report to critical evaluation. The adverse and inappropriate effects that the publication of clinical trial results can have on medical practice were discussed in an editorial by Kaplan, who pointed out the heavy responsibilities that fall on the shoulders of reviewers and journal editors to ensure that trials do not have serious design flaws and that their results are clearly and accurately reported. The publication in February 2011 of the results of a large, randomized study assessing the value of completion lymph node dissection (CLND) in sentinel node (SN)positive breast cancer patients illustrates how problems of misinterpretation can arise. The trial report was published in the Journal of the American Medical Association (JAMA), a leading international medical journal, and it was featured on the front page of the New York Times shortly afterwards. The title of the report in JAMA was ‘‘Axillary dissection versus no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial.’’ However, the dramatic headline in the New York Times read, ‘‘Lymph node study shakes pillar of breast cancer care,’’ and there were similar alarmist headlines in other major newspapers around the world. As a result of this widespread press publicity, we have encountered patients with melanoma who are not willing to consider entry into another large clinical trial, this one assessing the value of CLND when metastatic melanoma has been found in a SN (MSLT-II—Clinicaltrials.gov identifier NCT00297895). These patients have become aware that in the trial report in JAMA, Giuliano and colleagues concluded that CLND is not necessary for breast cancer patients found to be SN-positive. The patients assume that the situation for SN-positive melanoma patients will be the same, not understanding that the two tumor types behave in quite different ways, and that in any case all the SN-positive patients with breast cancer enrolled in the trial received radiation therapy to the axilla, and most (96.5 %) also received systemic chemotherapy (known to be effective for breast cancer, but not for melanoma). Another trial, published in a major medical journal in November 2009, also is having a major impact on clinical trial accrual in patients with metastatic melanoma, in this case those with cerebral metastases. The trial was reported by Chang and colleagues in Lancet Oncology and will be referred to hereafter as the Chang trial. It studied patients with cerebral metastases from cancers of various types who were treated with stereotactic radiosurgery (SRS) with or without whole brain radiotherapy (WBRT). The Chang trial was stopped early because one of six neurocognitive function assessment tools showed a detrimental result at 4 months. It is unknown whether this was a temporary or permanent effect of WBRT, because the trial was terminated before sufficient follow-up times had been achieved to assess long-term results. There are many potential pitfalls in the design, conduct, and reporting of clinical trials, and the Chang trial appears to have had several flaws. Some of these have been detailed in published correspondence, but there are a Society of Surgical Oncology 2012

Re-evaluation of a Scoring System to Predict Nonsentinel-Node Metastasis and Prognosis in Melanoma Patients

We previously developed a scoring system based on patient age and total sentinel node (SN) tumor size to predict nonsentinel node (NSN) metastasis. The score relied on the cutoff values of 55 years for age and 5 mm total SN tumor size to stratify SN-positive patients into 3 categories. Its validity, however, remains in doubt given that it was developed by retrospective review of a single, relatively small cohort of SN-positive melanoma patients. The purpose of this study was to validate this scoring system and to determine its value in predicting patient survival. A review of melanoma patients who had undergone sentinel node biopsy and completion lymph node dissection (CLND) at the Melanoma Institute Australia from June 1992 until April 2009 was undertaken. The significance of the correlation of each of the score variables (age and total SN tumor size) with NSN metastasis, melanoma-specific survival, and overall survival was tested. Cox logistic regression analysis was used to determine the degree of correlation of the score system to each of the 3 outcomes. Six hundred six SN-positive patients were identified and included in this study. The score system did not significantly correlate with NSN metastasis (p = 0.1049). However, it did significantly correlate with both overall survival (p < 0.0001) and disease-specific survival (p = 0.0014). Our results revealed that the previously developed scoring system does not predict NSN metastasis; however, it was found to be a powerful predictive tool for overall and disease-free survival in SN-positive melanoma patients.

Multimarker Reverse Transcriptase-Polymerase Chain Reaction Assay in Lymphatic Drainage and Sentinel Node Tumor Burden

PurposeWe assessed molecular (presence of melanoma cells markers in lymph fluid [LY]) and pathological features (sentinel lymph node [SN] tumor burden according to Rotterdam criteria, metastases microanatomic location) and correlated them with survival and melanoma prognostic factors in a group of patients with positive SN biopsy.MethodsWe analyzed 368 consecutive SN-positive patients after completion lymph node dissection (CLND). In 321 patients we obtained data on SLN microanatomic location/tumor burden (only 7 cases had metastases <0.1 mm); in 137 we additionally analyzed 24-hour collected LY after CLND (multimarker reverse transcriptase-polymerase chain reaction [MM-RT-PCR] with primers for tyrosinase, MART1 (MelanA), and uMAGE mRNA (27.7% positive samples)]. Median follow-up time was 41 months.ResultsAccording to univariate analysis, the following factors had a negative impact on overall survival (OS): higher Breslow thickness (P = .0001), ulceration (P < .0001), higher Clark level (P = .008), male gender (P = .0001), metastatic lymph nodes >1 (P < .0001), nodal metastases extracapsular extension (P < .0001), metastases to additional non-SNs (P = .0004), micrometastases size ≥0.1 mm (P = .0006), and positive LY MM-RT-PCR (P = .0007). SN tumor burden showed linear correlation with increasing Breslow thickness (P = .01). The 5-year OS rates for SLN tumor burden <0.1 mm, 1–1.0 mm, and >1.0 mm were 84%/66%/44%, respectively, and for positive and negative LY MM-RT-PCR 47%/0%, respectively. The independent factors for shorter OS (multivariate analysis): male gender, primary tumor ulceration, number of involved nodes ≥4, micrometastases size >1.0 mm, and, in additional model including molecular analysis—positive MM-RT-PCR results (hazard ratio [HR] 3.2), micrometastases size >1.0 mm (HR 1.13), and primary tumor ulceration (HR 2.17). Similar results were demonstrated for disease-free survival (DFS) data.ConclusionsSN tumor burden categories according to Rotterdam criteria and the positive result of LY MM-RT-PCR assay demonstrated additional, independent prognostic value in SN-positive melanoma patients, showing significant correlation with shorter DFS and OS.

Sentinel Node Positive Melanoma Patients: Prediction and Prognostic Significance of Nonsentinel Node Metastases and Development of a Survival Tree Model

Completion lymph node dissection (CLND) following positive sentinel node biopsy (SNB) for melanoma detects additional nonsentinel node (NSN) metastases in approximately 20% of cases. This study aimed to establish whether NSN status can be predicted, to determine its effect on survival, and to develop survival tree models for the sentinel node (SN) positive population. Sydney Melanoma Unit (SMU) patients with at least 1 positive SN, meeting inclusion criteria and treated between October 1992 and June 2005, were identified from the Unit database. Survival characteristics, potential predictors of survival, and NSN status were assessed using the Kaplan-Meier method, Cox regression model, and logistic regression analyses, respectively. Classification tree analysis was performed to identify groups with distinctly different survival characteristics. A total of 323 SN-positive melanoma patients met the inclusion criteria. On multivariate analysis, age, gender, primary tumor thickness, mitotic rate, number of positive NSNs, or total number of positive nodes were statistically significant predictors of survival. NSN metastasis, found at CLND in 19% of patients, was only predicted to a statistically significant degree by ulceration. Multivariate analyses demonstrated that survival was more closely related to number of positive NSNs than total number of positive nodes. Classification tree analysis revealed 4 prognostically distinct survival groups. Patients with NSN metastases could not be reliably identified prior to CLND. Prognosis following CLND was more closely related to number of positive NSNs than total number of positive nodes. Classification tree analysis defined distinctly different survival groups more accurately than use of single-factor analysis.